Enabled clinical use of an HIV-1 attachment inhibitor through drug delivery.

Abstract:

:The clinical advancement of HIV-1 attachment inhibitors was hindered initially by poor bioavailability. Attempts to identify improved candidates revealed that solubility and dissolution-rate-limited absorption are barriers to achieving adequate antiviral plasma levels. This was mitigated by forming nanosized drugs or by creating stabilised amorphous drug-polymer composites. In further improving drug potency and mitigating solubility-limited bioavailability, a candidate based on a phosphate ester prodrug was identified that, although having excellent bioavailability, exhibited unacceptable pharmacokinetics. Based on in silico modelling and a site of absorption study it was confirmed that creating an extended release formulation could provide the desired pharmacokinetic profile. The optimised formulation showed good antiviral activity when dosed employing a once or twice a day regimen.

journal_name

Drug Discov Today

journal_title

Drug discovery today

authors

Timmins P,Brown J,Meanwell NA,Hanna GJ,Zhu L,Kadow JF

doi

10.1016/j.drudis.2014.03.025

subject

Has Abstract

pub_date

2014-09-01 00:00:00

pages

1288-93

issue

9

eissn

1359-6446

issn

1878-5832

pii

S1359-6446(14)00119-6

journal_volume

19

pub_type

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